1. Field of the Invention
This invention is directed to new organic compounds and is particularly concerned with novel compounds IV (substituted 7-phenyl-12-triazino[4,3-a][1,4[benzodiazepine-1(5H)-ones) and intermediates and a process for the production thereof.
The novel compounds and the process of production therefor can be illustratively represented as follows: ##STR6## wherein R.sub.o is hydrogen, alkyl of 1 to 3 carbon atoms, inclusive, --C.sub.n H.sub.2n OR, in which n in an integer of 1 to 3, inclusive, and R is hydrogen or methyl, ##STR7## in which n is defined as before and R.sub.6 and R.sub.7 are hydrogen or alkyl as defined above, or together ##STR8## is pyrolidino, piperidino, morpholino, or ##STR9## in which R.sub.8 is methyl, ethyl, or 2-hydroxyethyl, ##STR10## in which m is an integer of 0 to 3, inclusive, and R.sub.9 is hydrogen, lower alkyl of from 1 to 4 carbon atoms, inclusive, wherein R.sub.1 is hydrogen or methyl; wherein R.sub.2 is phenyl, o-chlorophenyl, o-fluorophenyl, 2,6-difluorophenyl, or 2-pyridyl; wherein R.sub.3 is hydrogen, fluoro, chloro, bromo, trifluoromethyl, or nitro.
Alternatively, if in compound III, R.sub.9 is hydrogen, then before cyclization, compound III can be converted to an imidazolide by treatment with a carbonyldiazolide (for example 1,1'-carbonyldiimidazole). This imidazolide will cyclize spontaneously or by heating to produce compound IV wherein R.sub.0, R.sub.1, R.sub.2, and R.sub.3 are defined as above.
The invention also embraces the pharmacologically acceptable acid addition salts of compound of formula III and IV.
The process of this invention comprises: reacting a 2-hydrazinobenzodiazepine compound of formula I with an .alpha.-ketocarboxylic acid or its ester (formula II) in an inert organic solvent at 10.degree.-80.degree. C. to obtain a compound of formula III. Compound III wherein R.sub.10 is hydrogen can be converted to compound III wherein R.sub.10 is lower alkyl by esterification (for example with a diazoalkane). Compound III can be converted to compound IV by heating in an inert or acidic solvent at a temperature of 25.degree.-260.degree.. If desired compound III wherein R.sub.10 is hydrogen can be converted to the imidazolide and cyclized by heating in an inert solvent at a temperature between 0.degree. and 100.degree. C. to obtain compound IV.
Compounds IV, where R.sub.0 is ##STR11## (m and R.sub.9 as defined above) can be converted to compounds IV where R.sub.0 is ##STR12## (m, R.sub.6 and R.sub.7 as defined above) by the following processes:
1. When R.sub.0 is C.sub.m H.sub.2m COOH then this compound can be treated with diphenylphosphonylazide followed by rearrangement to the isocyanate, followed by hydrolysis to IV (R.sub.0 = C.sub.m H.sub.2m NH.sub.2) using procedures well known in the art for the Curtius or Schmidt reactions ["Organic Reactions" Vol. III, John Wiley and Sons, Inc. New York, NY., 1946, pages 307-451]. If desired IV (R.sub.0 = C.sub.m H.sub.2m NH.sub.2) can be alkylated in known manners.
2. IV (R.sub.0 = C.sub.m H.sub.2m COOH) can alternately be converted to IV (R.sub.0 = C.sub.m H.sub.2m NH.sub.2) via the acid chloride, p-nitrophenyl ester or imidazolide then to the azide followed by rearrangement and hydrolysis as above.
Compounds IV in which R.sub.0 is C.sub.n H.sub.2n OH (n as defined above) can be treated with SOCl.sub.2, PBr.sub.3 or ClSO.sub.2 R.sub.10 (R.sub.10 = alkyl or aryl) and base to give IV (R.sub.0 = C.sub.n H.sub.2n Cl, C.sub.n H.sub.2n Br or C.sub.n H.sub.2n OSO.sub.2 R.sub.10). This reactive intermediate can then be treated with ##STR13## to give IV ##STR14## wherein R.sub.6 and R.sub.7 are defined above).
Compounds IV in which R.sub.0 is CH.sub.3 can be converted to IV in which R.sub.0 is ##STR15## (R.sub.6 and R.sub.7 as defined above except at least one R.sub.6 or R.sub.7 is not H) by the Mannich reaction which consists in treatment of IV (r.sub.o = H) with formaldehyde and a primary or secondary amine ##STR16## usually as an acid addition salt) or with ##STR17## + acetylchloride.
The procedures for the Mannich reaction are well known to those skilled in the art ["Organic Reactions", Vol. I, John Wiley and Sons, New York, NY., 1942, pages 303-341; ibid. Vol. VII, 1953, pages 99-197].
Compounds IV in which R.sub.0 is CH.sub.3 can be converted to IV in which R.sub.0 is ##STR18## (R.sub.6 and R.sub.7 as defined above) by bromination followed by treatment with